<p>Neural stress responses play a critical role in the relapse of major depressive disorder (MDD); moreover, emerging findings suggest that the neural stress responses in both healthy adults and MDD patients are sex-dependent. However, whether the neural stress responses are related to future MDD relapse and whether relapse-related neural stress responses are sex-dependent remains unclear. Seventy-four first-episode unmedicated MDD patients completed the Montreal Imaging Stress Task (MIST) during functional magnetic resonance imaging at baseline. Two years after the initial recruitment, the relapse status of MDD patients was evaluated. Based on prior findings, the medial orbitofrontal cortex, amygdala, hippocampus, nucleus accumbens, and dorsolateral prefrontal cortex were selected as regions of interest; the overall brain activation and activation changes with stress exposure were extracted for each region. Our study included 31 MDD patients (15 male/16 female) with relapse and 43 MDD patients without relapse (17 male/26 female). Independent sample t-tests revealed that the relapse MDD group exhibited a higher increase in NAc activation with stress exposure (female and whole sample) and dlPFC activation (male sample) during MIST compared to the non-relapse MDD group. Logistic regression analyses revealed that the dlPFC activation positively predicted the future relapse in the male MDD group but not the female MDD group. Findings highlight that MDD relapse-related neural stress responses are sex-dependent, particularly for the potentiated stress-induced dlPFC activation for males and increased NAc activation with stress exposure for females.</p>